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1284 Spectrum of Hematological Malignancies in 130 Patients with Germline Predisposition Syndromes - Mayo Clinic Germline Predisposition Study

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Poster I
Hematology Disease Topics & Pathways:
Leukemia, ALL, Follicular Lymphoma, AML, Adult, Diseases, CLL, Lymphoma (any), CML, Bone Marrow Failure, GVHD, CMML, biopsy, Genetic Disorders, Non-Hodgkin Lymphoma, MDS, Pediatric, immunodeficiency, DLBCL, MPN, Immune Disorders, Technology and Procedures, thrombocythemia, cytogenetics, Lymphoid Malignancies, Study Population, Myeloid Malignancies, flow cytometry, NGS, radiation
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Emma Catherine Difilippo, BS1, Alejandro Ferrer, PhD2*, Laura Schultz-Rogers, PhD3*, Naseema Gangat, MBBS4, Shakila P Khan, MD5, Aref Al-Kali, MD4, Abhishek A. Mangaonkar, MBBS4, Animesh Pardanani, MBBS, PhD4, Michelle Elliot, MD6*, Mark Litzow, MD4, William J Hogan, MB, BCh7, Alexandra P. Wolanskyj, MD4*, Phuong L. Nguyen, MD8, Kaaren K. Reichard, MD9*, Matthew T Howard, MD4*, Rebecca L. King, MD8, Dong Chen, M.D., Ph.D.8, Rong He, MD8, David S. Viswanatha, MD8, Terra Lasho, PhD4, Rajiv K. Pruthi, M.B.B.S4, Pavel Pichurin6*, Teresa Kruisselbrink, MS6*, Brendan Lanpher, MD6*, Mark E Wylam, MD10*, Jennifer L. Oliveira, MD9, Dusica Babovic-Vuksanovic, MD6*, Horatiu Olteanu, MD, PhD8* and Mrinal M. Patnaik, MD, MBBS4

1Mayo Clinic Alix School of Medicine, Rochester, MN
2Center for Individualized Medicine, Department of Health Sciences Research, Mayo Clinic, Rochester
3Center for Individualized Medicine, Mayo Clinic, Rochester, MN
4Division of Hematology, Mayo Clinic, Rochester, MN
5Division of Pediatric Hematology, Mayo Clinic, Rochester, MN
6Mayo Clinic, Rochester, MN
7Mayo Clinic Rochester, Division of Hematology, Rochester, MN
8Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
9Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
10Division of Pulmonary & Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN


Germline predisposition syndromes (GPS) are inherited disorders associated with germinal aberrations that increase the risk of malignancies. While aberrations in certain genes increase the risk for all types of malignancies (Tp53, ATM, CDKN2A, CHEK2), there is a growing list of genes associated specifically with hematological malignancies (GATA2, RUNX1, DDX41, ETV6, ANKRD26). At our institution, we have established a hematology GPS clinic to diagnose and manage GPS and with this report, detail our experience with 130 patients.


GPS were investigated in pediatric and adult patients with one or more first degree relatives with hematological/visceral malignancies or in those with antecedent thrombocytopenia (ANKRD26, RUNX1, ETV6), or with specific syndromic features (short telomere syndromes/STS, GATA2 haploinsufficiency, Fanconi anemia/FA, Shwachman-Diamond syndrome/SDS). Depending on the phenotype, specific functional assays such as flow-FISH for telomere length assessment and chromosomal breakage assays were ordered. After informed consent and genetic counselling, germline testing was carried out on peripheral blood mononuclear cell, skin fibroblast, or hair follicle-derived DNA. A custom-designed marrow failure NGS panel (200 genes) was used in most cases and interrogation of variants, in silico studies, and functional assays were carried out as previously described (Mangaonkar et al MC Proc 2019). Copy number variations were identified by aCGH. At the time of progression/worsening cytopenias, bone marrow/lymph node biopsies and NGS (next generation sequencing) were carried out where indicated.


130 patients with germline predisposition have been identified to date. The spectrum of disorders seen include STS 29 (22%), FA 17 (13%), GATA2 16 (12%), Diamond Blackfan anemia/DBA 13 (10%), RUNX1-FPD 12 (9%), ATM deletions/mutations 11 (8%), ANKRD26 6 (5%), SDS 5 (4%), DDX41 4 (3%), MPL 3 (2%), CHEK2, MECOM, Tp53 mutations 2 (2%) each, and CBL, CEPBA, ELANE, NF1, CDKN2A, CSF3R, ETV6, and GATA1 mutations, 1 (1%) each.

Evidence for clonal evolution (CCUS) and hematological malignancies were seen in 51 (39%) patients, involving all the aforementioned genes/syndromes with the exception of DBA, CBL, ETV6, MPL, CSF3R, and GATA1.

Seven (64%) of 11 patients with germline ATM deletions/mutations developed lymphoid malignancies; homozygous ATM (Follicular NHL-1, Burkitt lymphoma-1, T-ALL-1, T-LPD-1) and heterozygous ATM (T-PLL-1, DLBCL-1, CLL-1). Clonal evolution occurred in 11 (69%) of 16 GATA2 haploinsufficient patients (CCUS-2, MDS-3, CMML-1, AML-5) and in 7 (58%) of 12 RUNX1-FPD patients (CCUS-1, MDS-1, MDS/MPN-3, AML-2). Five of 29 (17%) STS patients had clonal progression (CCUS-2, MDS-2, AML-1), and 5 (29%) of 17 FA patients progressed to MDS-2 or AML-3. JMML was seen in one patient with a germline NF1 mutation, while 1 (20%) of 5 SDS patients progressed to AML.

NGS data at progression was available in 24 (55%) of 44 myeloid/CCUS progressions, with somatic truncating ASXL1 mutations being most frequent (29%), followed by RAS pathway mutations (15%). AML/MDS progressions in STS, FA, and SDS were universally associated with complex/monosomal karyotypes, translating to refractory disease. Seventeen (39%) of 44 patients with myeloid predisposition underwent allogenic HCT (GATA2-7, FA-3, RUNX1-FPD-3, STS-2, NF1-1, Tp53-1), with 10 (59%) being alive at last follow up (Table 1).


We demonstrate the spectrum of germline aberrations associated with predisposition to hematological malignancies and outline the phenotypic heterogeneity of clonal transformation. The advent of NGS allows identification of clonal progression earlier than morphological changes, with mutations in ASXL1 and RAS pathway genes being commonly implicated. This study supports the universal development of dedicated germline predisposition clinics.

Disclosures: Pruthi: Merck: Honoraria; Instrumentation Laboratory: Honoraria; HEMA Biologics: Honoraria; Bayer Healthcare: Honoraria; Genentech Inc.: Honoraria; CSL Behring: Honoraria.

*signifies non-member of ASH